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Interspecies interactions are known to activate specialized metabolism in diverse actinomycetes. However, how interspecies cues are sensed and ultimately lead to induction of specialized metabolite biosynthetic gene clusters remains largely unexplored. Using transcriptome sequencing (RNA-seq), we analyzed genes that were transcriptionally induced in the model actinomycete  Streptomyces coelicolor  during interactions with four different actinomycetes, including genes that encode unusual regulatory systems known as conservons. Deletions in one such system, encoded by the  cvn8  genes, led to altered patterns of pigmented antibiotic production by  S. coelicolor  during interactions. Further transcriptomic analysis of mutants lacking each of the five genes in the  cvn8  locus demonstrated that this system is a global regulator of at least four different specialized metabolite biosynthetic pathways. How conservon systems work at the mechanistic level to regulate gene expression is not well understood, although it has been hypothesized that they may function in a way similar to eukaryotic G-protein-coupled receptors. The data presented here indicate that the gene products of the  cvnA8  and  cvnF8  (SCO6939) genes likely function together in one part of the Cvn8 signaling cascade, while the  cvnC8  and  cvnD8  gene products likely function together in another part. Importantly, because  cvnD8  likely encodes a Ras-like GTPase, these results connect G-protein-mediated signaling to gene regulation in a bacterium. Additionally, deletion of any of the  cvn8  genes led to abnormally high expression of an adjacent cryptic lanthipeptide biosynthetic gene cluster, indicating that conservon systems may be fruitful targets for manipulation to activate silent specialized metabolite biosynthetic pathways.   IMPORTANCE  Interactions between different species of actinomycete bacteria often trigger one of the strains to produce specialized metabolites, such as antibiotics. However, how this induction occurs at the genetic level is poorly understood. Using transcriptomic methods, we show that an unusual regulatory system, known as a conservon system, is responsible for regulating expression of multiple specialized metabolite biosynthetic gene clusters in the organism  Streptomyces coelicolor  during interactions. Conservon systems are unusual because they appear to employ small GTPases as an important component of their signaling cascades. Small GTPases are common in eukaryotic signaling pathways, but the results presented here are notable since they implicate a system that includes a small GTPase in global gene regulation in a bacterium. Mutants lacking this conservon system also showed abnormally high expression of a gene cluster involved in making an unknown specialized metabolite, suggesting that conservon mutants might be useful for driving natural product discovery.

The cvn8 Conservon System Is a Global Regulator of Specialized Metabolism in Streptomyces coelicolor during Interspecies Interactions